CN102078305A - 苯达莫司汀冻干药物组合物 - Google Patents
苯达莫司汀冻干药物组合物 Download PDFInfo
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- CN102078305A CN102078305A CN2010106217593A CN201010621759A CN102078305A CN 102078305 A CN102078305 A CN 102078305A CN 2010106217593 A CN2010106217593 A CN 2010106217593A CN 201010621759 A CN201010621759 A CN 201010621759A CN 102078305 A CN102078305 A CN 102078305A
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- bendamustine
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- freeze
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Abstract
本发明提供了苯达莫司汀冻干药物组合物。本发明进一步提供了生产冻干苯达莫司汀的方法。该药物制剂可以用于任何对苯达莫司汀的治疗敏感的疾病,例如肿瘤性疾病。
Description
本申请为国际申请PCT/US2006/001308于2007年7月16日进入中国国家阶段、申请号为200680002440.4、发明名称为“苯达莫司汀冻干药物组合物”的分案申请。
技术领域
本发明涉及用于治疗各种疾病状态,尤其是肿瘤性疾病和自身免疫性疾病的药物组合物的领域。特别是,本发明涉及包括氮芥,尤其是氮芥苯达莫司汀,例如盐酸苯达莫司汀的药物制剂。
背景技术
本发明要求2005年1月14日提交的名为“苯达莫司汀药物组合物(Bendamustine Pharmaceutical Compositions)”的美国申请60/644,354的优先权,其以全文,包括附图和权利要求书引入本文作为参考。
以下说明包括可能对理解本发明有用的信息。并不是承认任何这些信息是现有技术或与本申请要求保护的发明相关,或者在本申请中具体或者暗示引用的出版物是现有技术。
氮芥由于其在水溶液中的高度反应性,难以配制成药品,其常常以冻干的形式供应给药,冻干的形式需要在给药前由熟练的医院工作人员进行复溶,通常用水复溶。一旦处于水溶液中,氮芥就容易因为水解作用而降解,因此,复溶的产物必须在其复溶后尽可能快地向患者给药。
苯达莫司汀,(4-{5-[二(2-氯乙基)氨基]-1-甲基-2-苯并咪唑基}丁酸是具有苯并咪唑环的非典型结构,其结构中含有活性氮芥(见式I,其显示的是盐酸苯达莫司汀)
式I
苯达莫司汀最初合成于1963年德意志民主共和国(GDR),从1971年至1992年在该地区可以商品名Cytostasan买到。从那时以后,苯达莫司汀在德国以商品名Ribomustin上市。苯达莫司汀已在德国广泛使用于治疗慢性淋巴细胞性白血病、霍奇金病(Hodgkin′s disease)、非霍奇金淋巴瘤(non-Hodgkin′s lymphoma)、多发性骨髓瘤和乳腺癌。
由于其在水溶液中降解(与其它氮芥类似),苯达莫司汀以冻干产品的形式供应。现有苯达莫司汀的冻干制剂(Ribomustin)在白色粉末的无菌冻干形式中含有盐酸苯达莫司汀和甘露醇,用于复溶后静脉内使用。冻干制剂成品暴露于光线时不稳定。因此,该产品保存在棕色或琥珀色小瓶中。现有苯达莫司汀的冻干制剂含有可能在原料药的生产期间和/或在制成药物成品的冻干过程中出现的降解产物。
目前,苯达莫司汀被配制成每个50mL的小瓶中含有100mg药物或者每个20mL的小瓶中含有25mg药物的注射用冻干粉末。打开小瓶并复溶的时间尽可能地与患者用药的时间接近。产品用40mL(对于100mg规格)或10mL(对于25mg规格)的无菌注射用水复溶。复溶产物进一步用500mL足量0.9%氯化钠注射液稀释。给药途径为静脉输注30-60分钟。
用40mL无菌注射用水复溶后,小瓶中的苯达莫司汀在室温储存下稳定7小时,或在2-8℃储存下稳定6天。500mL的混合溶液必须在小瓶复溶后的7小时内向患者给药(假定混合物在室温下储存)。
现有苯达莫司汀冻干粉末复溶困难。临床报道显示,复溶需要至少15分钟,并可能需要长达30分钟。除了对于负责复溶该产品的健康护理专业人士来说麻烦和费时之外,由于水对该产品的水解作用,复溶过程中苯达莫司汀在水中过长时间的暴露增加了失效和杂质形成的可能性。
因此,存在着对易于复溶,并且具有比现有苯达莫司汀冻干制剂(冻干粉末)更好的杂质分布的苯达莫司汀冻干制剂的需求。
德国(GDR)专利No.34727公开了制备1位取代的ω-[5-二-(β-氯乙基)-氨基-苯并咪唑基-(2)]-链烷羧酸的方法。
德国(GDR)专利No.80967公开了γ-[1-甲基-5-二-(β-氯乙基)-氨基-苯并咪唑基-(2)]-丁酸盐酸盐的注射剂。
德国(GDR)专利No.159877公开了制备4-[1-甲基-5-二(2-氯乙基)氨基-苯并咪唑基-2]-丁酸的方法。
德国(GDR)专利No.159289公开了苯达莫司汀的注射液。
Ribomustin苯达莫司汀产品专题材料(2002年1月更新)http://www.ribosepharm.de/pdf/ribomustin_bendamustin/productmonograp h.pdf提供了有关Ribomustin的信息,包括产品说明书。
Ni等人报道,亚硝基脲SarCNU在纯叔丁醇中比在纯乙酸、二甲基亚砜、甲醇(methylhydroxy)、水或TBA/水混合物中更稳定(Ni et al.(2001)Intl.J.Phamaceutics 226:39-46)。
冻干环磷酰胺是本领域公知的,参见例如美国专利No.5,418,223;5,413,995;5,268,368;,227,374;5,130,305;4,659,699;4,537,883和5,066,647。
冻干氮芥异环磷酰胺(Ifosfamide)公开于国际出版物No.WO 2003/066027;美国专利No.6,613,927;5,750,131;5,972,912;5,227,373和5,204,335中。
Teagarden等人公开了通过将PGE-1溶解在乳糖和叔丁醇的溶液中而制成的前列腺素E-1的冻干制剂(美国专利No.5,770,230)。
发明概述
本发明涉及稳定的氮芥的药物组合物,尤其是冻干苯达莫司汀,以及其在治疗各种疾病状态,尤其是肿瘤性疾病和自身免疫性疾病中的应用。
本发明的一个实施方案是苯达莫司汀的药物组合物,其在释放时含有不大于约0.5%至约0.9%(占苯达莫司汀的面积百分数)的HP1,如式II所示,
式II
或者其中所述HP1是在本文所述苯达莫司汀的冻干药物组合物复溶后的零时存在的HP1的量。在优选实施方案中,苯达莫司汀的药物组合物含有不大于约0.5%(占苯达莫司汀的面积百分比)的HP1,优选不大于约0.45%,较优选不大于约0.40%,更优选不大于约0.35%,最优选不大于0.30%。
本发明的另一个实施方案是在释放或复溶后的零时含有不大于约0.1%至约0.3%的苯达莫司汀二聚体的苯达莫司汀冻干制剂,所述二聚体见式III所示。
式III
本发明的另一个实施方案是在释放或复溶后的零时含有不大于约0.5%,优选0.15%至约0.5%的苯达莫司汀乙酯的苯达莫司汀冻干制剂,所述苯达莫司汀乙酯见式IV所示。
式IV
本发明的另一个实施方案是苯达莫司汀冻干制剂,其中苯达莫司汀乙酯(式IV)的浓度不大于0.2%,优选0.1%,大于在用来制备冻干制剂的原料药中发现的苯达莫司汀乙酯的量。
在本发明的另一个实施方案中,苯达莫司汀冻干制剂在药品释放时含有不大于约0.5%至约0.9%(占苯达莫司汀的面积百分比)的HP1。在优选实施方案中,苯达莫司汀冻干制剂含有不大于约0.50%(占苯达莫司汀的面积百分比)的HP1,优选不大于约0.45%,更优选不大于约0.40%,更优选不大于约0.35%,甚至更优选不大于0.30%。该实施方案的一方面是苯达莫司汀冻干制剂在药品释放时含有不大于约0.5%至约0.9%,优选0.5%(占苯达莫司汀的面积百分比)的HP1,其中冻干制剂包装在小瓶或其它药学上可接受的容器中。
本发明的另一个方面,就HP1的量而言,苯达莫司汀冻干制剂在约2℃至约30℃储存时保持稳定至少约6个月,优选12个月,优选24个月,至约36个月或更长时间。优选储存温度为约5℃和接近室温。
本发明的另一个实施方案是包括苯达莫司汀的药物组合物的药物剂型,所述药物组合物含有不大于约0.5%至约0.9%的HP1,优选不大于约0.50%,更优选不大于约0.45%,更优选不大于约0.40%,更优选不大于约0.35%,甚至更优选不大于0.30%,其中HP1是在释放时或本发明的苯达莫司汀冻干制剂复溶后的零时存在的HP1的量。在本发明的优选方面,剂型可以为约5至约500mg苯达莫司汀,约10至约300mg苯达莫司汀,约25mg苯达莫司汀,约100mg苯达莫司汀和约200mg苯达莫司汀。
本发明的另一个实施方案是包括含有不大于约0.5%至约0.9%,优选0.5%的HP1的苯达莫司汀冻干制剂的药物剂型。优选剂型可以为约5至约500mg苯达莫司汀,约10至约300mg苯达莫司汀,约25mg苯达莫司汀,约100mg苯达莫司汀和约200mg苯达莫司汀。
在另一个实施方案中,本发明包括苯达莫司汀的药物组合物,该药物组合物包括含有HP1不大于约0.50%至约0.9%(占苯达莫司汀的面积百分比),优选不大于约0.5%,较优选不大于约0.45%,更优选不大于约0.40%,更优选不大于约0.35%,甚至更优选不大于0.30%的苯达莫司汀,以及一种或多种痕量有机溶剂,其中所述HP1是释放时或在本文所公开苯达莫司汀冻干药物组合物复溶后的零时存在的HP1的量。在该实施方案的不同方面,有机溶剂选自叔丁醇、正丙醇、正丁醇、异丙醇、乙醇、甲醇、丙酮、乙酸乙酯、碳酸二甲酯、乙腈、二氯甲烷、甲基乙基甲酮、甲基异丁基甲酮、1-戊醇、乙酸甲酯、四氯化碳、二甲基亚砜、六氟丙酮、氯丁醇、二甲基砜、乙酸和环己烷中的一种或多种。优选有机溶剂包括乙醇、甲醇、丙醇、丁醇、异丙醇和叔丁醇中的一种或多种。更优选的有机溶剂是叔丁醇,也称作TBA。
本发明包括使苯达莫司汀产品获得机构批准的方法,改进包括建立苯达莫司汀降解物小于约4.0%,优选约2.0%至约4.0%(占苯达莫司汀的面积百分比)的释放质量标准,或以其它方式获得本文所述药物组合物。该实施方案的一个方面是使苯达莫司汀产品获得机构批准的方法,包括建立HP1小于或等于1.5%(占苯达莫司汀的面积百分比)的释放质量标准。本文中苯达莫司汀产品在释放时含有不大于约0.5%(占苯达莫司汀的面积百分比)的HP1。
另一个实施方案是使苯达莫司汀产品获得机构批准的方法,改进包括建立苯达莫司汀降解物小于约7.0%,优选约5.0%至约7.0%(占苯达莫司汀的面积百分比)的货架期质量标准,其中产品在约2℃至约30℃储存。优选储存温度为约5℃和约室温。本文中苯达莫司汀产品在释放时含有不大于约0.5%(占苯达莫司汀的面积百分比)的HP1。
本发明的另一个实施方案是制造苯达莫司汀冻干制剂的方法,其包括控制成品中苯达莫司汀降解物的浓度,例如释放时苯达莫司汀降解物的浓度小于约4.0%,优选不大于约2.0%至约4.0%(占苯达莫司汀的面积百分比),或者以其它方式获得本文所述药物组合物。本文中苯达莫司汀产品在释放时含有不大于约0.5%至约0.9%,优选约0.5%(占苯达莫司汀的面积百分比)的HP1。
本发明公开了制造苯达莫司汀冻干制剂的方法,其包括控制成品中苯达莫司汀降解物的浓度,例如,释放时HP1的浓度小于约0.9%,优选0.5%(占苯达莫司汀的面积百分比),在产品有效期满时,苯达莫司汀降解物的浓度小于约7.0%,优选不大于约5.0%至约7.0%;其中所述产品在约2℃至约30℃储存。
本发明的另一个实施方案是包括一种或多种有机溶剂的苯达莫司汀冻干前溶液或分散体,其中溶液或分散体包括至少一种稳定浓度的有机溶剂,该有机溶剂降低苯达莫司汀的降解水平,从而使约0-24小时冻干期间产生的HP1的量不超过约0.5%至约0.9%(占苯达莫司汀的面积百分比),优选0.50%,较优选0.45%,更优选0.40%,更优选0.35%,甚至更优选0.30%。该实施方案的一个方面是由冻干前溶液或分散体生产的冻干粉末。
本发明的另一个实施方案是包括一种或多种有机溶剂的苯达莫司汀冻干前溶液或分散体,其中溶液或分散体包括至少一种稳定浓度的有机溶剂,该有机溶剂降低苯达莫司汀的降解水平,从而使约0-24小时冻干期间产生的苯达莫司汀乙酯的量不超过约0.5%(占苯达莫司汀的面积百分比)。该实施方案的一个方面是由冻干前溶液或分散体生产的冻干粉末。
本发明的另一个实施方案是包括一种或多种有机溶剂的苯达莫司汀冻干前溶液或分散体,其中溶液或分散体包括至少一种稳定浓度的有机溶剂,该有机溶剂降低苯达莫司汀的降解水平,从而使约0-24小时冻干期间产生的苯达莫司汀乙酯(如式IV所示)的量不大于0.2%,优选0.1%,大于在用来制备冻干前溶液的原料药中发现的苯达莫司汀乙酯的浓度。优选有机溶剂是叔丁醇。
本发明还公开了制备苯达莫司汀冻干制剂的方法,包括将苯达莫司汀溶解在稳定浓度的含有约5%至约100%(v/v)醇的醇溶剂中制成冻干前溶液;以及将冻干前溶液冷冻干燥;其中用这些方法制成的苯达莫司汀冻干制剂含有不大于约0.5%至约0.9%,优选0.5%(占苯达莫司汀的面积百分比)的式II所示的HP1,其中所述HP1是释放时或在苯达莫司汀冻干药物组合物复溶后的零时存在的HP1的量。其它醇浓度包括约5%至99.9%,约5%至约70%,约5%至约60%,约5%至约50%,约5%至约40%,约20%至约35%。优选醇浓度为约20%至约30%。优选醇包括甲醇、乙醇、丙醇、异丙醇、丁醇和叔丁醇中的一种或多种。更优选的醇是叔丁醇。叔丁醇的优选浓度为约20%至约30%,优选约30%。该实施方案的一个方面是在冻干前加入赋形剂。优选赋形剂是甘露醇。优选冻干前苯达莫司汀的浓度为约2mg/mL至约50mg/mL。
在制备苯达莫司汀冻干制剂的优选方法中,将冻干前溶液冷冻干燥包括i)将冻干前溶液冷冻至低于约-40℃,优选-50℃的温度,以形成冷冻溶液;ii)使冷冻溶液保持在-40℃或低于-40℃,优选-50℃的温度至少2小时;iii)将冷冻溶液缓慢调节温度至约-40℃至约-10℃的第一干燥温度,以形成干燥溶液;iv)维持约10至约70个小时;v)将干燥溶液缓慢调节温度至约25℃至约40℃的第二干燥温度;以及vii)维持约5至约40小时,以形成苯达莫司汀冻干制剂。在更优选方法中,将冻干前溶液冷冻干燥包括i)将冻干前溶液冷冻至约-50℃,以形成冷冻溶液;ii)使冷冻溶液保持在约-50℃至少2小时至约4小时;iii)缓慢调节温度至约-20℃至约-12℃的第一干燥温度,以形成干燥溶液;iv)维持在第一干燥温度约10至约48个小时;v)将干燥溶液缓慢调节温度至约25℃至约40℃的第二干燥温度;以及vii)维持在第二干燥温度至少5小时至约20小时。优选醇为叔丁醇。叔丁醇的优选浓度为约20%至约30%,优选约30%。该实施方案的一个方面是在冻干前加入赋形剂。优选赋形剂是甘露醇。优选冻干前苯达莫司汀的浓度为约2mg/mL至约50mg/mL。
本发明的另一个实施方案是通过本文公开的制备苯达莫司汀冻干制剂的方法获得的冻干粉末或制剂。
本发明还包括用于冻干的苯达莫司汀制剂,其包括赋形剂和稳定浓度的有机溶剂。优选该制剂包括浓度约15mg/mL的苯达莫司汀,浓度约25.5mg/mL的甘露醇、浓度约30%(v/v)的叔丁醇和水。本发明的该实施方案中包括由这些苯达莫司汀制剂制成的冻干制剂。
本发明包括治疗患者的医学病症的方法,包括给予有效治疗量的本发明的药物组合物,其中病症对所述药物组合物的治疗敏感。一些可以用本发明的组合物治疗的病症包括慢性淋巴细胞性白血病(CLL)、霍奇金病、非霍奇金淋巴瘤(NHL)、多发性骨髓瘤(MM)、乳腺癌、小细胞肺癌、过度增生性病症和自身免疫性疾病。优选病症包括NHL、CLL、乳腺癌和MM。优选自身免疫性疾病包括类风湿性关节炎、多发性硬化症或狼疮。
本发明包括本发明的药物组合物或药物制剂在生产用于治疗患者的本文所定义医学病症的药剂中的应用,该治疗包括给予有效治疗量的本发明的药物组合物,其中病症对所述药物组合物的治疗敏感。
本发明还包括本发明的药物组合物与一种或多种抗肿瘤剂联合的治疗方法,其中抗肿瘤剂在本发明的药物组合物给药之前、同时或之后给予。优选抗肿瘤剂是CD20的特异性抗体。
本发明另一个实施方案是生产本发明的苯达莫司汀冻干制剂的冻干周期。优选冻干周期包括a)在约8小时内冷冻至约-50℃;b)保持在-50℃约4小时;c)在约3小时内调节温度至-25℃;d)在-10℃保持30小时;e)在约3小时内调节温度至约25℃至约40℃或更高温度;f)保持在约25℃至约40℃约25小时;g)在1小时内调节温度至约20℃;h)在约20℃,13.5psi的压力下卸载样品至药学上可接受的密封容器中;其中第一次干燥期间的压力为约150微米,第二次干燥期间的压力为50微米。该周期的一方面包括步骤(e),其在3小时内调节温度至约30-35℃,然后在5小时内调节温度至40℃。该实施方案的另一个方面是由这种冻干周期制成的冻干粉末。更优选的冻干周期包括i)开始在约5℃的搁架温度下装载样品;ii)在约8小时内冷冻至约-50℃;iii)保持在-50℃约4小时;iv)在约3小时内调节温度至约-20℃;v)在约-20℃保持6小时;在约1小时内调节温度至约-15℃;vi)保持在-15℃约20小时;vii)在约1小时内调节温度至约-15℃;viii)保持在约-15℃约20小时;ix)在约0.5小时内调节温度至约-12℃;x)保持在约-12℃约15.5小时;xi)在约15小时内调节温度至约25℃至约40℃或更高;xii)保持在约25℃至约40℃约10小时;xiii)在约1小时内调节温度至约40℃;以及xiv)保持在约40℃约5小时;在约5℃,约13.5psi的压力下卸载样品至药学上可接受的密封容器中,其中第一次干燥期间的压力为约150微米,第二次干燥期间的压力为50微米。在优选实施方案中,步骤(xi)是在约15小时内调节温度至约30-35℃。
本发明还包括苯达莫司汀的药物剂型,该苯达莫司汀含有不大于约0.5%至约0.9%,优选0.5%的HP1(占苯达莫司汀的面积百分比),其中所述剂型包括小瓶或其它药学上可接受的容器,其中所述HP1是所述剂型在复溶前或复溶后的零时存在的HP1的量。优选苯达莫司汀浓度包括约10至约500mg/容器,约100mg/容器,约5mg至约2g/容器,以及约170mg/容器。
本发明还包括苯达莫司汀的冻干前药物组合物。优选冻干前组合物包括约15mg/mL的盐酸苯达莫司汀,约25.5mg/mL的甘露醇,约30%(v/v)的叔丁醇和水。
以下描述了本发明的这些实施方案及其它实施方案,根据下列公开内容,本发明的这些实施方案及其它实施方案对本领域技术人员而言是容易理解的。
附图说明
图1显示了不同温度下两种不同苯达莫司汀的叔丁醇溶液中苯达莫司汀的溶解性。
图2显示了苯达莫司汀在不同醇中于5℃孵育24小时后的HPLC纯度分析结果。结果以占苯达莫司汀峰的面积百分比表示。
图3显示了在5℃于不同醇/水共溶剂中24小时后HP1(式II)的形成情况。
图4显示了在5℃于不同醇/水共溶剂中24小时后二聚体(式III)的形成情况。
图5显示了使用TBA/水共溶剂的苯达莫司汀冻干周期。
发明内容
本文所用术语“配制”是指适于向哺乳动物,优选人类患者给药的形式的药品,例如苯达莫司汀的制备。因此,“配制”可以包括药学上可接受的赋形剂、稀释剂或载体的加入。
本文所用术语“冻干粉末”或“冻干制剂”是指任何经冻干,即水溶液的冷冻干燥得到的固体物质。水溶液可以含有非水溶剂,即,溶液由水和一种或多种非水溶剂组成。优选冻干制剂是这样的冻干制剂,即其中的固体物质是将含水和一种或多种非水溶剂的溶液冷冻干燥后获得的,更优选非水溶剂是醇。
“稳定的药物组合物”是指任何具有足以使其具有作为医药产品的实用性的稳定性的药物组合物。优选稳定的药物组合物具有这样的稳定性,其足以允许在合适的温度,优选-20℃至40℃,更优选约2℃至约30℃下储存合理的时间,例如产品的货架期,其可以是1个月那样短,但通常为6个月或更长时间,较优选1年或更长时间,更优选24个月或更长时间,甚至更优选36个月或更长时间。货架期或有效期可以是活性成分降解至低于90%纯度的点的时间长度。为了本发明的目的,稳定的药物组合物包括具有本文所述特定杂质范围的药物组合物参照。优选稳定的药物组合物是活性成分降解最小的药物组合物,例如,其在2-30℃储存2-3年的时间后保有至少约85%的未降解活性成分,优选至少约90%,更优选至少约95%。
“稳定的冻干制剂”是指任何具有足以使其具有作为医药产品的实用性的稳定性的冻干制剂,其特征与本文对稳定的药物组合物定义的类似。
“降解”是指活性成分在化学结构上发生变化。
本文所用术语“有效治疗量”是指将在某种程度上减轻被治疗病症的一种或多种症状的被给药化合物的量。对于肿瘤物的治疗,有效治疗量是指具有以下作用的量:(1)减小肿瘤大小,(2)抑制(即,在某种程度上延缓,优选停止)肿瘤转移,(3)在某种程度上抑制(即,在某种程度上延缓,优选停止)肿瘤生长,和/或(4)在某种程度上缓解(或者,优选消除)与癌症相关的一种或多种症状。有效治疗量也可以指预防可能易感染疾病但仍未经历或表现出该疾病的症状的动物发生疾病的量(预防性治疗)。此外,有效治疗量可以是增加患有致死病症患者的预期寿命的量。通常用于治疗非霍奇金淋巴瘤的苯达莫司汀有效治疗量可以是单剂量给予约60-120mg/m2,连续给药两天。该周期可以约每3-4周重复一次。对于慢性淋巴细胞性白血病(CLL)的治疗,可以在第1和第2天给予苯达莫司汀约80-100mg/m2。该周期可以在约4周后重复。对于霍奇金病(II-IV期)的治疗,可以按照“DBVBe方案”给予苯达莫司汀,即,在第1和第15天给予柔红霉素25mg/m2,博来霉素10mg/m2和长春新碱1.4mg/m2,并在第1-5天给予苯达莫司汀50mg/m2,约每4周重复该周期一次。对于乳腺癌,第1和第8天给予苯达莫司汀(120mg/m2),并在第1和第8天联合给予甲氨喋呤40mg/m2和5-氟尿嘧啶600mg/m2,约每4周重复该周期一次。作为乳腺癌的二线治疗,可以在第1和第2天给予苯达莫司汀约100-150mg/m2,约每4周重复该周期一次。
本文用到的“肿瘤”是指异常生长的肿瘤物,这种生长因为不受到通常的生长限制的细胞增殖而发生。本文用到的“抗肿瘤剂”是指任何抑制、消除、延缓或逆转细胞的肿瘤性表型的化合物、组合物、混合物、共混合物或掺合物。
本文用到的“过度增生”是指应答特定生长因子的细胞的过度产生。“过度增生性病症”是其中细胞应答特定生长因子而过度产生的疾病。这种“过度增生性病症”的例子包括糖尿病性视网膜病、银屑病、子宫内膜异位症、癌症、黄斑退行性疾病和良性生长病症,例如前列腺增大。
本文所用术语“小瓶”是指任何坚硬或柔韧的有壁容器。
本文用到的“控制”是指在适当的地方设置过程控制,以促进被控制事物的完成。例如,在指定情况下,“控制”可以指有规律地或者随机地测试各批样品或多批样品;将降解物浓度设为释放质量标准;选择工艺条件,例如在冻干前溶液或分散体中使用醇和/或其它有机溶剂,以确保活性成分的降解物浓度不是不可接受地高;等。通过对降解物的量建立释放质量标准来控制降解物,可以用来使医药产品容易通过管理机构,例如美国食品药品监督管理局和其它国家或地区的类似机构的批准。
本文所用术语“药学上可接受的”是指药学上可接受的事物,例如药物组合物的组分,包括容器,不导致不可接受的药理活性的缺失或者不可接受的不良副作用。药学上可接受的组分的例子在由位于马里兰州Rockville的美国药典委员会在1990年通过的美国药典(USP),国家处方集(NF)和美国食品药品监督管理局出版的FDA非活性成分指南(Inactive Ingredient Guide)1990,1996(均因此引入本文作为参考,包括任何图片)中提供。符合必要限制和/或质量标准的USP/NF之外的其它级别的溶液或组分也可以使用。
本文所用术语“药物组合物”应该指在使其适于向人类给药的条件下制成的组合物,例如在GMP条件下制备,药物组合物包括药学上可接受的赋形剂,例如但不限于稳定剂、填充剂、缓冲剂、载体、稀释剂、介质、增溶剂和粘合剂。本文用到的药物组合物包括但不限于冻干前溶液或分散体,以及冻干制剂复溶后准备用于注射或输注的液体形式。
本文用到的“药物剂型”是指本文公开的药物组合物在容器中,并且其量适于复溶和单剂量或多剂量给药,通常为约1-2、1-3、1-4、1-5、1-6、1-10或约1-20个剂量。优选地,本文所用“药物剂型”是指本文公开的冻干药物组合物在容器中,并且其量适于复溶和单剂量或多剂量递送,通常为约1-2、1-3、1-4、1-5、1-6、1-10或约1-20个剂量。药物剂型可以包括小瓶或注射器或其它适合的药学上可接受的容器。适于注射或输注使用的药物剂型可以包括含有活性成分的无菌水溶液或分散体,或者适合临时制备无菌注射用或输注用溶液或分散体的无菌粉末。在所有情况下,最终的剂型应该是无菌液体,并且在生产和储存条件下稳定。液体载体或介质可以是溶剂或液体分散介质,包括例如水、乙醇、多元醇,例如甘油、丙二醇或液体聚乙二醇等、植物油、无毒甘油酯及其适宜的混合物。对微生物生长的抑制可以通过各种抗细菌剂和抗真菌剂,例如对羟基苯甲酸酯、氯丁醇、苯酚、山梨酸、柳硫汞等来完成。
本文所用术语“赋形剂”是指用于将活性药物成分(API)配制成药物制剂的物质;在优选实施方案中,赋形剂不降低或干扰API的主要治疗作用。优选赋形剂是治疗上惰性的。术语“赋形剂”包括载体、稀释剂、介质、增溶剂、稳定剂、填充剂和粘合剂。赋形剂还可以是作为制造过程的间接或非预期结果而存在于药物制剂中的物质。优选赋形剂被批准或被认为对人和动物给药是安全的,即,GRAS物质(一般认为安全)。GRAS物质由食品药品监督管理局在联邦管理法规(Code of Federal Regulations,CFR)的21 CFR§182和21 CFR§184中列出,其引入本文作为参考。优选赋形剂包括但不限于己糖醇,包括甘露醇等。
本文用到的“稳定浓度的有机溶剂”或“稳定浓度的醇”是指减少苯达莫司汀的降解水平以达到药品成品中降解物的特定水平的有机溶剂或醇的量。例如,对于降解物HP1,稳定浓度的有机溶剂是导致HP1的浓度(占苯达莫司汀的面积百分比)小于约0.5%,优选小于0.45%,较优选小于0.40%,更优选小于0.35%,更优选小于0.30%,甚至更优选小于0.25%的量。对于药品成品的全部或总降解物浓度,稳定浓度的有机溶剂是导致总降解物浓度(药品释放时)小于约7%(占苯达莫司汀的面积百分比),优选小于约6%,更优选小于约5%,最优选小于约4.0%的量。“占苯达莫司汀的面积百分比”是指通过例如HPLC测定时,特定降解物,例如HP1相对于苯达莫司汀的量。
术语“有机溶剂”是指通常为液体,能溶解其它物质的有机材料。
本文用到的“痕量有机溶剂”是指溶剂的量等于或低于医药产品的推荐水平,例如,ICH指南推荐的水平(International Conferences on Harmonization,Impurities--Guidelines for Residual Solvents.Q3C.Federal Register.1997;62(247):67377)。下限是可检出的最小量。
术语“释放”是指药品符合释放质量标准,可以用于其预期药学目的。
A.概要
本发明提供了由苯达莫司汀制备的稳定的药学上可接受的组合物。尤其是,本发明提供了用于冻干盐酸苯达莫司汀的制剂。由这类制剂得到的冻干粉末比目前市售的苯达莫司汀冻干粉末更容易复溶。此外,就某些杂质,尤其HP1、苯达莫司汀二聚体和苯达莫司汀乙酯而言,本发明的冻干产品在复溶前,冻干品(lyophilate)储存后,或者复溶和混合后具有比Ribomustin更好的杂质分布。
本发明进一步提供了用于治疗肿瘤性疾病的苯达莫司汀制剂。本文所述该制剂可以单独给药,或者与至少一种额外的抗肿瘤剂和/或放射疗法联合给药。
本发明的一方面是提高苯达莫司汀在冻干工艺之前和冻干工艺期间、货架期或复溶后的稳定性的条件和方法。
可以与本发明的制剂联合使用的抗肿瘤剂包括Merck Index 11,pp 16-17,Merck & Co.,Inc.(1989)和The Chemotherapy Source Book(1997)中提供的抗肿瘤剂。两本书均是本领域技术人员广泛公认并且容易得到的。
有大量处于商业应用、临床评价和临床前开发中的抗肿瘤剂可以选择用于通过联合药物化学疗法治疗瘤形成。这些抗肿瘤剂属于几种主要类别,即,抗生素类药剂、DNA共价结合药物、抗代谢剂、激素类药剂,包括糖皮质激素,例如泼尼松和地塞米松、免疫剂、干扰素类药剂、分化剂,例如类视黄醇、促细胞凋亡剂和其它药剂,包括化合物例如反义小干扰RNA等。另外,可以使用其它抗肿瘤剂,例如金属基质蛋白酶(MMP)抑制剂、SOD模拟物或αvβ3抑制剂。
可以与本发明的化合物联合使用的一类抗肿瘤剂由抗代谢类抗肿瘤剂组成。适宜的抗代谢类抗肿瘤剂可以选自由阿拉诺新、AG2037(Pfizer公司)、5-FU-纤维蛋白原、acanthifolic acid、氨基噻二唑、布喹那钠、卡莫氟、Ciba-Geigy CGP-30694、环戊基胞嘧啶、磷酸阿糖胞苷硬脂酸酯(cytarabine phosphate stearate)、阿糖胞苷共轭物、Lilly DATHF、Merrel Dow DDFC、地扎胍宁、双脱氧胞苷、双脱氧鸟苷、didox、Yoshitomi DMDC、去氧氟尿苷、Wellcome EHNA、Merck & Co.EX-015、法扎拉滨、氟尿嘧啶脱氧核苷、磷酸氟达拉滨、5-氟尿嘧啶、N-(2′-呋喃烷基)-5-氟尿嘧啶、Daiichi Seiyaku FO-152、异丙基吡咯里嗪(pyrrolizine)、Lilly LY-188011、Lilly LY-264618、methobenzaprim、甲氨喋呤、Wellcome MZPES、norspermidine、NCI NSC-127716、NCI NSC-264880、NCI NSC-39661、NCI NSC-612567、Warner-Lambert PALA、喷司他丁、吡曲克辛、普卡霉素、Asahi Chemical PL-AC、Takeda TAC-788、硫鸟嘌呤、噻唑呋林、Erbamont TIF、三甲曲沙、酪氨酸激酶抑制剂、酪氨酸蛋白激酶抑制剂、Taiho UFT和uricytin组成的组。
可以与本发明的化合物联合使用的第二类抗肿瘤剂由DNA共价结合剂组成。适宜的烷化类抗肿瘤剂可以选自由Shionogi 254-S、醛磷酰胺类似物、六甲密胺、阿那昔酮、Boehringer Mannheim BBR-2207、bestrabucil、布度钛、Wakunaga CA-102、卡铂、卡莫司汀、Chinoin-139、Chinoin-153、苯丁酸氮芥、顺铂、环磷酰胺、American Cyanamid CL-286558、Sanofi CY-233、cyplatate、Degussa D-19-384、Sumimoto DACHP(Myr)2、二苯基螺莫司汀、diplatinum cytostatic、Erba偏端霉素衍生物、Chugai DWA-2114R、ITI E09、依莫司汀、Erbamont FCE-24517、雌氮芥磷酸钠、福莫司汀、Unimed G-6-M、Chinoin GYKI-17230、hepsul-fam、异环磷酰胺、异丙铂、洛莫司汀、马磷酰胺、美法仑、二溴卫矛醇、Nippon Kayaku NK-121、NCI NSC-264395、NCI NSC-342215、奥沙利铂、Upjohn PCNU、泼尼莫司汀、Proter PTT-119、雷莫司汀、司莫司汀、SmithKline SK&F-101772、Yakult Honsha SN-22、螺莫司汀、Tanabe Seiyaku TA-077、牛磺莫司汀、替莫唑胺、替罗昔隆、四铂和三甲密醇组成的组。
可以与本文公开的化合物联合使用的另一类抗肿瘤剂由抗生素类抗肿瘤剂组成。适宜的抗生素类抗肿瘤剂可以选自由Taiho 4181-A、阿柔比星、放射菌素D、游放线酮、阿拉诺新、Erbamont ADR-456、aeroplysinin衍生物、Ajinomoto AN-201-II、Ajinomoto AN-3、Nippon Soda茴香霉素、蒽环类、连氮霉素A、重溶癌菌素、Bristol-Myers BL-6859、Bristol-Myers BMY-25067、Bristol-Myers BMY-25551、Bristol-Myers BMY-26605、Bristol-Myers BMY-27557、Bristol-Myers BMY-28438、硫酸博来霉素、苔藓抑素-1、Taiho C-1027、calichemycin、chromoximycin、放线菌素D、柔红霉素、Kyowa Hakko DC-102、Kyowa Hakko DC-79、Kyowa Hakko DC-88A、Kyowa Hakko DC89-Al、Kyowa Hakko DC92-B、二丙八叠红菌素B、Shionogi DOB-41、多柔比星、多柔比星-纤维蛋白原、爱萨霉素A、表柔比星、制表菌素、依索比星、埃斯波霉素A1、埃斯波霉素Alb、Erbamont FCE-21954、Fujisawa FK-973、福司曲星、Fujisawa FR-900482、滑杆菌素、聚头孢素A、灰肉红霉素、除莠霉素、伊达比星、隐杯伞素、上总霉素、kesarirhodins、Kyowa Hakko KM-5539、Kirin Brewery KRN-8602、Kyowa Hakko KT-5432、Kyowa Hakko KT-5594、Kyowa Hakko KT-6149、AmericanCyanamid LL-D49194、Meiji Seika ME 2303、美诺立尔、丝裂霉素、米托蒽醌、SmithKline M-TAG、新拟定菌素、Nippon Kayaku NK-313、Nippon Kayaku NKT-01、SRI International NSC-357704、噁溶菌素、oxaunomycin、培洛霉素、必杯菌素、吡柔比星、porothramycin、pyrindamycin A、Tobishi RA-I、雷怕霉素、根霉素、罗多比星、西班米星、siwenmycin、Sumitomo SM-5887、Snow Brand SN-706、Snow Brand SN-07、堆囊菌素A、司帕霉素、SS Pharmaceutical SS-21020、SS Pharmaceutical SS-7313B、SS Pharmaceutical SS-9816B、司替霉素B、Taiho 4181-2、他利霉素、Takeda TAN-868A、类萜菌素、thrazine、tricrozarin A、Upjohn U-73975、Kyowa Hakko UCN-10028A、Fujisawa WF-3405、Yoshitomi Y-25024和佐柔比星组成的组。
可以与本发明的化合物联合使用的第四类抗肿瘤剂包括其它抗肿瘤剂,其选自由α-胡萝卜素、α-二氟甲基精氨酸、阿维A、三氧化二砷、Avastin(贝伐单抗)、Biotec AD-5、Kyorin AHC-52、鸡骨常山碱、氨萘非特、amphethinile、安吖啶、Angiostat、ankinomycin、抗瘤酮A10、抗瘤酮A2、抗瘤酮A3、抗瘤酮A5、抗瘤酮AS2-1、Henkel APD、阿非迪霉素甘氨酸盐、门冬酰胺酶、Avarol、燕茜素、batracylin、benfluron、氯苯酰色氨酸、Ipsen-Beaufour BIM-23015、比生群、Bristo-Myers BMY-40481、Vestar boron-10、bromofosfamide、Wellcome BW-502、Wellcome BW-773、卡醋胺、carmethizole氢氯化物、Aiinomoto CDAF、chlorsulfaquinoxalone、Chemes CHX-2053、Chemex CHX-100、Warner-Lambert CI-921、Warner-Lambert CI-937、Warner-Lambert CI-941、Warner-Lambert CI-958、克兰氟脲、claviridenone、ICN化合物1259、ICN化合物4711、Contracan、Yakult Honsha CPT-11、克立那托、curaderm、细胞松弛素B、阿糖胞苷、cytocytin、Merz D-609、DABIS马来酸酯、达卡巴嗪、datelliptinium、代代宁B、二血卟啉醚、二氢仑哌隆(dihydrolenperone)、地那林、偏端霉素、Toyo Pharmar DM-341、Toyo Pharmar DM-75、Daiichi Seiyaku DN-9693、elliprabin、依利醋铵、epothionesTsumura EPMTC、erbitux、麦角胺、erlotnib、依托泊苷、阿维A酯、芬维A胺、Fujisawa FR-57704、硝酸镓、芫花烯、Gleevec(imatnib)、Chugai GLA-43、Glaxo GR-63178、gefitinib、灰树花多糖NMF-5N、十六烷胆碱磷酸、Green Cross HO-221、高三尖杉酯碱、羟基脲、BTG ICRF-187、indanocine、伊莫福新、异谷酰胺、异维A酸、Otsuka JI-36、Ramot K-477、Otsuak K-76COONa、Kureha Chemical K-AM、MECT Corp KI-8110、American Cyanamid L-623、白细胞调节素、氯尼达明、Lundbeck LU-23-112、Lilly LY-186641、NCI (US)MAP、marycin、甲氟喹、Merrel Dow MDL-27048、Medco MEDR-340、硫巴比妥苯胺、部花青衍生物、甲基苯胺基吖啶、Molecular Genetics MGI-136、minactivin、米托萘胺、米托喹酮、莫哌达醇、莫维A胺、Zenyaku Kogyo MST-16、N-(视黄酰基)氨基酸、Nisshin Flour Milling N-021、N-酰化脱氢丙氨酸、那法扎琼、Taisho NCU-190、诺考达唑衍生物、Normosang、NCI NSC-145813、NCI NSC-361456、NCI NSC-604782、NCI NSC-95580、奥曲肽、Ono ONO-112、oquizanocine、Akzo Org-10172、紫杉醇、pancratistatin、帕折普汀、Warner-Lambert PD-111707、Warner-Lambert PD-115934、Warner-Lambert PD-131141、Pierre Fabre PE-1001、ICRT肽D、吡罗蒽醌、聚血卟啉、polypreic acid、Efamol卟啉、吗丙嗪、丙卡巴肼、丙谷胺、Invitron蛋白酶连接素I、Tobishi RA-700、雷佐生、Sapporo Breweries RB S、restrictin-P、瑞替普汀、维A酸、Rhone-Poulenc RP-49532、Rhone-Poulenc RP-56976、Rituxan(及其它抗CD20抗体,例如BexxarZevalin)、SmithKline SK&F-104864、他汀类(Lipitor等)、Sumitomo SM-108、Kuraray SMANCS、SeaPharm SP-10094、spatol、螺环丙烷(spirocyclopropane)衍生物、锗螺胺、Unimed、SS Pharmaceutical SS-554、strypoldinone、Stypoldione、Suntory SUN 0237、Suntory SUN 2071、超氧化物歧化酶、沙利度胺、沙利度胺类似物、Toyama T-506、Toyama T-680、紫杉醇、Teijin TEI-0303、替尼泊苷、thaliblastine、Eastman Kodak TJB-29、生育三烯酸、Topostin、Teijin TT-82、Kyowa Hakko UCN-01、Kyowa Hakko UCN-1028、ukrain、Eastman Kodak USB-006、硫酸长春碱、长春新碱、长春地辛、vinestramide、长春瑞滨、长春曲醇、长春利定、睡茄交酯和Yamanouchi YM-534、Zometa组成的组。
可以与本发明的化学疗法联合使用的放射防护剂的例子有AD-5、adchnon、氨磷汀类似物、detox、地美司钠、1-102、MM-159、N-酰化脱氢丙氨酸、TGF-Genentech、噻丙莫德、氨磷汀、WR-151327、FUT-187、酮洛芬经皮制剂、萘丁美酮、超氧化物歧化酶(Chiron公司和Enzon公司)。
制备上述抗肿瘤剂的方法可以在文献中找到。例如美国专利No.3,590,028和4,012,448描述了制备多柔比星的方法。EP 780386描述了制备金属基质蛋白酶抑制剂的方法。WO 97/08174描述了制备αvβ3抑制剂的方法。
优选抗肿瘤剂包括但不限于柔红霉素、博来霉素、长春新碱、多柔比星、达卡巴嗪、泼尼松龙、米托蒽醌、泼尼松、甲氨喋呤、5-氟尿嘧啶、地塞米松、沙利度胺、沙利度胺衍生物、2ME2、新伐司他、R115777、三氧化二砷、硼替佐米、他莫昔芬、G3139(反义)和SU5416、丝裂霉素、抗CD20抗体,例如Rituxan和R-依托度酸中的一种或多种。
本发明的制剂可以与其结合使用,或者作为其中一种或多种组分的替代品使用的优选用药方案包括但不限于ABVD(多柔比星、博来霉素、长春新碱、达卡巴嗪)、DBV(柔红霉素、belomycin、长春新碱)、CVPP(环磷酰胺、长春碱、丙卡巴肼、泼尼松龙)、COP(环磷酰胺、长春新碱、泼尼松龙)、CHOP(环磷酰胺、多柔比星、长春新碱和泼尼松)和CMF(环磷酰胺、甲氨喋呤、5-氟尿嘧啶)。其它方案见下表A。
表A-癌症治疗方案
如本文描述的那样,苯达莫司汀的冻干制剂在除去水中的有机溶剂之后完成。用于制备该制剂的溶剂的最典型的例子是叔丁醇(TBA)。其它可以使用的有机溶剂包括乙醇、正丙醇、正丁醇、异丙醇、乙酸乙酯、碳酸二甲酯、乙腈、二氯甲烷、甲基乙基甲酮、甲基异丁基甲酮、丙酮、1-戊醇、乙酯甲酯、甲醇、四氯化碳、二甲基亚砜、六氟丙酮、氯丁醇、二甲基砜、乙酸、环己烷。上述这些溶剂可以单独或者联合使用。可用的溶剂必须与苯达莫司汀形成稳定的溶液,并且必须一点也不使API降解或失活。苯达莫司汀在选定溶剂中的溶解度必须足够地高,以在溶剂中形成商业上可用浓度的药物。此外,溶剂还应该能容易地从药品的水分散体或溶液中除去,例如,通过冷冻干燥或真空干燥。优选使用含有浓度约2-80mg/mL,优选约5至40mg/mL,更优选5-20mg/mL,最优选12至17mg/mL的苯达莫司汀的溶液。
药学上可接受的冻干赋形剂可以溶解在水相中。用于本发明的赋形剂的例子包括但不限于磷酸钠或磷酸钾、柠檬酸、酒石酸、明胶、甘氨酸和碳水化合物,例如乳糖、蔗糖、麦芽糖、甘油、右旋糖、葡聚糖、海藻糖和羟乙基淀粉。甘露醇是优选赋形剂。其它如果需要时可以使用的赋形剂包括抗氧化剂,例如但不限于抗坏血酸、乙酰半胱氨酸、半胱氨酸、亚硫酸氢钠、丁基羟基茴香醚、丁基羟基甲苯或乙酸α-生育酚,或螯合剂。
下文提供了依照本发明的典型制剂和冻干周期。冻干可以用用于冷冻干燥或真空干燥的标准设备进行。周期可以根据用于填充/整理的设备与设施的改变而改变。
依照本发明的典型实施方案,首先在药学上可接受的混合器皿中配制冻干前水溶液或水分散体。将该溶液无菌过滤至无菌容器中,然后填充到适宜大小的小瓶内,部分压塞后,装入冻干机中。采用本文所述冻干技术将溶液冷冻干燥,直至达到约0.1%至约8.0%的含水量。所得冻干粉末在约5℃至约25℃下作为冻干粉末保持稳定约6个月至大于约2年,优选大于约3年,并且可以容易地用无菌注射用水或其它适宜载体复溶,以提供苯达莫司汀的适于体内给药,例如胃肠外注射的液体制剂。对于静脉给药,复溶的液体制剂,即,药物组合物优选为溶液。
通常首先在药学上可接受的容器中通过下述步骤配制冻干前溶液或分散体:1)在环境温度下向水(约为总体积的65%)中边搅拌边加入赋形剂,例如甘露醇(约0至约50mg/mL),2)在约20℃-35℃下向水溶液中边搅拌边加入有机溶剂(0.5-99.9%,v/v),例如TBA,4)在搅拌下加入盐酸苯达莫司汀至预期浓度,5)加水至达到最终体积,以及6)冷却溶液至约1℃至约30℃,优选约5℃。尽管上述步骤以一定的顺序列出,但应该了解,本领域技术人员可以按照需要改变这些步骤的顺序和数量。数量也可以根据重量准备。
冻干前溶液或分散体可以在冻干前灭菌,灭菌一般通过无菌过滤,例如,通过0.22μm或更小孔径的滤膜来完成。可以采用多次无菌过滤。溶液或分散体的灭菌可以通过其它本领域已知的方法,例如辐射来完成。
在这种情况下,灭菌后,溶液或分散体即可进行冻干。一般来说,过滤后的溶液将被注入到无菌接收器皿中,然后转移至任何适宜的容器,在该容器中制剂被有效地冻干。制剂通常在产品上市时所用的容器,例如但不限于本文定义和本领域已知的小瓶中有效且高效地冻干。
下文阐明了用于将冻干前溶液或分散体冻干的典型程序。然而,本领域技术人员将了解,可以根据例如但不限于冻干前溶液或分散体及冻干设备这样的事物对该程序或过程进行修改。
首先,将产品置于在某个温度范围内的冻干室中,然后在远低于该产品的冰点的温度下保持通常数小时。优选温度在约-40℃或低于-40℃约至少2小时。冷冻完成后,用真空泵将冻干室和冷凝器抽成真空,冷凝器表面已预先用循环制冷剂冷却。优选冷凝器已冷却至溶液的冰点以下,优选约-40℃,更优选约-50℃或更低温度,最优选约-60℃或更低温度。此外,冻干室应持续抽真空,直至获得约10至约600微米,优选约50至约150微米的压力。
然后产品组合物在真空下于冻干室和冷凝器内加热。这通常在范围为约10至约600微米的压力下通过加热冻干机内的搁架来完成,在冻干过程中产品被搁置在搁架上。最理想的是,加热过程在数小时的时间内逐步进行。例如,产品温度最初应从约-30℃升高至约-10℃,并保持约10-70小时。此外,产品温度可以在30-192小时的时间内从冷冻温度升高至约25℃-40℃。为防止冻干粉末从小瓶中喷出,在初始干燥阶段必须完全除去有机溶剂和水。干燥完全可以通过真空度的稳定、冷凝器温度和产品搁架温度来确认。初始干燥之后,产品温度应升高至约25-40℃,并保持约5-40小时。
一旦干燥周期完成,冻干室的压力可以用无菌、干燥的氮气(或等同气体)缓慢释放至大气压(或略低于大气压)。如果产品组合物在例如小瓶这样的容器中冻干,则将小瓶压塞,移出并密封。取出几个代表性样品,用于完成各种物理、化学和微生物学检查,以分析产品质量的目的。
苯达莫司汀冻干制剂通常以药物剂型的形式上市。本发明的药物剂型尽管通常为小瓶的形式,但也可以是任何适宜的能保持无菌环境的容器,例如安瓿、注射器、共通瓶(co-vials)。这些容器可以是玻璃或者塑料的,条件是该材料不与苯达莫司汀制剂发生相互作用。封闭物通常是塞子,最典型的是无菌橡胶塞,优选为提供气密式封闭的溴化丁基橡胶塞。
可以在冻干后将苯达莫司汀冻干粉末装入容器,例如小瓶中,或者可以将冻干前溶液装入这些小瓶,并在其中冻干,从而导致这些小瓶中直接含有苯达莫司汀冻干制剂。在装入溶液并在其中将溶液冻干之后,将这些小瓶用例如塞子密封,以提供密封的无菌药物剂型。通常地,小瓶含有的冻干粉末中包括约10-500mg/瓶,优选约100mg/瓶的苯达莫司汀和约5mg-2g/瓶,优选约170mg/瓶的甘露醇。
本发明的冻干制剂可以用水,优选无菌注射用水,或其它无菌液体,例如共溶剂复溶,以提供适合给药,例如通过进一步稀释至适宜的静脉内混合容器,例如标准生理盐水之后经胃肠外注射的苯达莫司汀溶液。
B.溶解度
通过视觉检查测定盐酸苯达莫司汀(苯达莫司汀)在水及水与不同量的冻干常用醇,例如甲醇、乙醇、丙醇、异丙醇、丁醇和叔丁醇(TBA)中的溶解度。在室温下制备15mg/mL苯达莫司汀与25.5mg/mL甘露醇在10mL指定醇溶液中的溶液(见表1)。然后样品在5℃冷却,并在0、3、6及24小时后检查微粒和/或沉淀。
表1所示结果表明,苯达莫司汀的溶解度依赖于温度和水溶液中醇的量。对于测试的醇,当醇的浓度增加时,苯达莫司汀的溶解度增加。沉淀的形成也依赖于温度和时间。苯达莫司汀在任何醇中均不立即发生沉淀,但在5℃储存后产生结晶。各种醇对溶解度的影响不同。尽管不希望受到任何特定理论的限制,但小分子醇例如甲醇和乙醇与大分子醇(叔丁醇和正丁醇)相比,对溶解度的影响较小。然而,醇的类型也同样重要。例如,发现正丙醇比异丙醇更能预防该系统发生沉淀。对溶解度影响最大的两种醇是正丁醇和叔丁醇。
表1.在5℃储存时24小时内苯达莫司汀在不同醇中的溶解度
CCS代表无色澄清溶液。
图1和表2中概述了定量测定不同温度下苯达莫司汀在3种不同溶液中的溶解度的实验。实验中使用的TBA的量,20%(v/v)和30%(v/v)是以稳定性研究(结果在下文中描述)为基础的。对于测试的两种溶液,随着温度从25℃向0℃降低,苯达莫司汀的溶解度呈线性减小。该实验证实了表1中所示数据,并突出了20%和30%TBA溶液中苯达莫司汀溶解度的差异。
表2.苯达莫司汀在TBA中的溶解度
C.稳定性
由于其在水溶液中因为水的水解作用而导致的不稳定性,苯达莫司汀需要冻干以制成适于药用的产品。然而,在冻干药品的制造过程中,在冻干之前通常需要用水溶液来填充。因此,苯达莫司汀和其它氮芥的混合及填充过程中,水溶液的使用可以导致药品的降解。
因此,就不同醇对苯达莫司汀降解的影响进行了评价,以确定是否可以找到这样的制剂,该制剂允许更长的填充-整理时间,提供能比现有Ribomustin制剂复溶更快的冻干粉末,和/或提供就某些杂质,例如HP1和BM1二聚体而言比Ribomustin具有更好杂质分布的苯达莫司汀冻干制剂。
优选本发明的冻干制剂在约2℃至约30℃,优选5℃储存时,就HP1而言,在6个月,更优选12个月,甚至更优选大于24个月,例如36个月内保持稳定,即,HP1的量无明显增加(不超出货架期质量标准)。
表3显示了5℃下24小时内苯达莫司汀在未加入醇的水中的稳定性结果。苯达莫司汀在水中迅速降解,并主要形成水解产物HP1(单羟基苯达莫司汀)。
单羟基苯达莫司汀(HP1)
式II
表3.苯达莫司汀在水中的稳定性
持续时间 纯度(%面积) HP1(%) 二聚体(%)
0%醇,即只有水 0小时 99.11 0.60 0.11
3小时 98.83 0.86 0.13
6小时 98.44 1.22 0.17
24小时 95.67 3.81 0.29
在该研究和其它长期稳定性研究中观察到的其它主要降解物是苯达莫司汀的二聚体。
苯达莫司汀二聚体(BM1二聚体)
式III
Ribomustin冻干产品中含有的其它降解物是苯达莫司汀乙酯(BM1EE)(式IV)和BM1DCE(式V)。当苯达莫司汀与乙醇反应时形成BM1EE。
苯达莫司汀乙酯(BM1EE)
式IV
BM1DCE
式V
图2概述了5℃下苯达莫司汀在不同醇中孵育24小时后的HPLC纯度分析结果。结果以占总峰面积的百分数表示。图2的数值在表3-9中提供。不管什么醇,都是在含有较高浓度醇的溶液中纯度最高。在被评价的醇中,苯达莫司汀在含有约30%(v/v)TBA的溶液中降解最少。在约10%和约20%的醇溶液中,正丁醇在防止苯达莫司汀降解方面占优势。正丁醇在水中的浓度为20%和30%(v/v)时,由于在这些浓度下正丁醇在水中的不溶解性而产生了两相系统。
图3和图4显示了通过HPLC(如本文描述的那样)测得的苯达莫司汀降解的量,以HP1和二聚体的形成表示。不管什么醇,当醇浓度的量减少,HP1和二聚体的形成就增加。这种杂质增加的发生具有预期的时间依赖性(见表3-9)。叔丁醇和正丁醇看来在防止产品降解方面比其它醇占优势。如在表10中看到的那样,甘露醇对苯达莫司汀在TBA中的稳定性没有影响。
表4.苯达莫司汀在不同乙醇浓度下24小时稳定性的HPLC稳定性结果。HP1和二聚体是该研究中增加的杂质。
表5.苯达莫司汀在不同叔丁醇浓度下24小时的HPLC稳定性结果。HP1和二聚体是该研究中增加的杂质。
表6.苯达莫司汀在不同正丙醇浓度下24小时的HPLC稳定性结果。HP1和二聚体是该研究中增加的杂质。
表7.苯达莫司汀在不同异丙醇浓度下24小时的HPLC稳定性结果。HP1和二聚体是该研究中增加的杂质。
表8.苯达莫司汀在不同甲醇浓度下24小时的HPLC稳定性结果。HP1和二聚体是该研究中增加的杂质。
表9.苯达莫司汀在不同正丁醇浓度下24小时的HPLC稳定性结果。HP1和二聚体是该研究中增加的杂质。
a-在小瓶中两种溶液均具有2层/相液体。制备样品前将溶液涡旋。
表1-9的结果表明,就HP1和二聚体而言,盐酸苯达莫司汀的稳定性随着醇浓度的增加而提高。
表10.苯达莫司汀在有或无甘露醇的TBA中24小时的HPLC稳定性结果
注意:分析无甘露醇样品用的是正相HPLC法,而分析有甘露醇样品用的是反相HPLC法。从分析其它样品的结果可以看出,这两种方法之间差异很小。
D.冻干周期的建立
各种浓度的苯达莫司汀、甘露醇和醇的水溶液制备不同的冻干前制剂。如本文描述的那样,在冷冻(快对慢)、第一次干燥(温度和压力)和第二次干燥的每一步对周期进行改变和优化。
根据上述所有溶解度、稳定性和冻干容易度方面的信息,优选制剂包括:
成分 浓度
苯达莫司汀 约2-40mg/mL
甘露醇 约0-50mg/mL
醇 约0.5%-40%(v/v)
水适量至 预期体积
其中醇选自甲醇、正丙醇或异丙醇
成分 浓度
苯达莫司汀 约5-20mg/mL
甘露醇 10-30mg/mL
醇 1-20%(v/v)
水适量至 预期体积
其中醇选自甲醇、正丙醇或异丙醇
成分 浓度
苯达莫司汀 约5-20mg/mL
甘露醇 10-30mg/mL
醇 5-40%(v/v)
水适量至 预期体积
成分 浓度
盐酸苯达莫司汀 约12-17mg/mL
甘露醇 约20-30mg/mL
醇 约5-15%(v/v)
水适量至 预期体积
成分 浓度
盐酸苯达莫司汀 约15mg/mL
甘露醇 约25.5mg/mL
醇 约10%(v/v)
水适量至 预期体积
成分 浓度
盐酸苯达莫司汀 约2-40mg/mL
甘露醇 约0-50mg/mL
丁醇 约0.5-20%(v/v)
水适量至 预期体积
成分 浓度
盐酸苯达莫司汀 约5-20mg/mL
甘露醇 约10-30mg/mL
丁醇 约1-10%(v/v)
水适量至 预期体积
成分 浓度
盐酸苯达莫司汀 约12-17mg/mL
甘露醇 约20-30mg/mL
丁醇 约1-10%(v/v)
水适量至 预期体积
成分 浓度
盐酸苯达莫司汀 约15mg/mL
甘露醇 约25.5mg/mL
丁醇 约10%(v/v)
水适量至 预期体积
成分 浓度
盐酸苯达莫司汀 约2-50mg/mL
甘露醇 约0-50mg/mL
叔丁醇 约0.5-100%(v/v)
水适量至 预期体积
成分 浓度
盐酸苯达莫司汀 约2-50mg/mL
甘露醇 约0-50mg/mL
叔丁醇 约0.5-99.9%(v/v)
水适量至 预期体积
成分 浓度
盐酸苯达莫司汀 约2-50mg/mL
甘露醇 约0-50mg/mL
叔丁醇 约0.5-99%(v/v)
水适量至 预期体积
成分 浓度
盐酸苯达莫司汀 约2-50mg/mL
甘露醇 约0-50mg/mL
叔丁醇 约90-99%(v/v)
水适量至 预期体积
成分 浓度
盐酸苯达莫司汀 约5-20mg/mL
甘露醇 约10-30mg/mL
叔丁醇 约5-80%(v/v)
水适量至 预期体积
成分 浓度
盐酸苯达莫司汀 约12-17mg/mL
甘露醇 约20-30mg/mL
叔丁醇 约10-50%(v/v)
水适量至 预期体积
成分 浓度
盐酸苯达莫司汀 约12.5-15mg/mL
甘露醇 约0-30mg/mL
乙醇 约20-30%(v/v)
水适量至 预期体积
成分 浓度
盐酸苯达莫司汀 约15mg/mL
甘露醇 约25.5mg/mL
叔丁醇 约30%(v/v)
水适量至 预期体积
实施例
下面提供的实施例是为了说明本发明的某些方面,并帮助本领域技术人员实施本发明。决不能认为这些实施例是以任何方式限制本发明的范围。
原料:
盐酸苯达莫司汀(Degussa公司,批号#0206005和0206007)甘露醇,NF级,或等同物(Mallinckrodt公司)
无水乙醇(100%),USP级,或等同物(Spectrum公司)
叔丁醇,ACS(EM Science公司)
甲醇(Spectrum公司和EMD公司)
丙醇(Spectrum公司)
异丙醇(Spectrum公司)
丁醇(Spectrum公司)
水,HPLC级,或等同物(EMD公司)
乙腈,HPLC级,或等同物(EMD公司)
三氟乙酸,J.T.Baker公司
甲醇,HPLC级,或等同物(EM Science公司,目录号#MX0488P-1)
三氟乙酸,HPLC级,或等同物(JT Baker公司,目录号JT9470-01)
设备:
带有光电二极管阵列检测器的Waters 2695 Alliance HPLC系统带有双波长检测器的Waters 2795 Alliance HPLC系统
分析天平(Mettler AG285,ID号#1028和Mettler XS205)
AdVantage型VirTis冻干机
Agilent Zorbax SB-C18柱,5μm,4.6×250mm,目录号#880975-902
实施例1-HPLC程序
方法1
流动相A:0.1%TFA;H2O
流动相B:0.1%TFA;50%ACN∶50%H2O
UV:230nm
流速:1.0mL/min
柱温:30℃
样品温度:5℃
进样体积:10μL
样品浓度:0.25mg/mLde MeOH溶液
梯度:20%B,保持1min
23min内,20%B-90%B
90%B,保持6min
1min内,恢复至20%B
20%B,保持4min
运行时间:30min
运行后时间:5min
方法2
流动相A:0.1%TFA;H2O∶ACN(9∶1)
流动相B:0.1%TFA;H2O∶ACN(5∶5)
UV:230nm
流速:1.0mL/min
柱温:30℃
样品温度:5℃
进样体积:10μL
样品浓度:0.25mg/mL的MeOH溶液
梯度:0%B,保持3min
13min内,0%B-50%B
17min内,50%B-70%B
2min内,70%B-90%B
90%B,保持5min
1min内,恢复至0%B
0%B,保持4min
运行时间:40min
运行后时间:5min
方法3
相A:HPLC级水,含0.1%TFA(v/v)
相B:HPLC级ACN/水(1∶1,v/v),含0.1%TFA(v/v)
UV:254nm
流速:1.0mL/min
柱温:30℃
样品温度:5℃
进样体积:5μL
采集时间:30min
采集后时间:9min
稀释剂:甲醇
梯度:
时间(min) 流动相A,% 流动相B,%
0.0 82 18
7.0 60 40
11.0 60 40
15.0 20 80
30.0 20 80
31.0 82 18
样品的制备:将药品用200mL甲醇溶解。超声处理6分钟。溶液可以直接注入HPLC(计算值0.5mg/mL).
方法4
相A:HPLC级水,含0.1%TFA(v/v)
相B:HPLC级ACN,含0.1%TFA(v/v)
UV:254nm
流速:1.0mL/min
柱:Zorbax Bonus RP-C14,5μm,4.6×150mm
柱温:30℃
样品温度:5℃
进样体积:2μL
采集时间:31min
采集后时间:5min
稀释剂:NMP/0.1%TFA水溶液(50∶50,v/v)
梯度:
时间(min) 流动相A,% 流动相B,%
0.0 93 7
5 93 7
13 73 27
16 73 27
25 10 90
31 10 90
方法4的样品制备:将药品用已知量的稀释剂溶解,制成浓度为4.2mg/mL的溶液直接注入HPLC。为了获得4.2mg/mL的样品浓度,可能必须进行第二次稀释(100mg/小瓶的剂型)。
结果
表11:用HPLC法1获得的苯达莫司汀及其某些杂质的保留时间
样品名称 保留时间(min)
HP1 14.110
苯达莫司汀 22.182
BM1二聚体 24.824
BM1EE 26.968
尽管HPLC法1能分离在苯达莫司汀中发现的杂质,但其不能分离在分析期间形成的潜在杂质,苯达莫司汀甲酯(BM1ME)。BM1ME与BM1二聚体的保留时间仅相差0.3分钟。为了分离BM1二聚体,开发了另一种HPLC法(方法#2)。HPLC法#2能分离所有杂质,但需要长达45min的运行时间(表12)。
表12:用HPLC法2获得的苯达莫司汀及杂质的保留时间
样品名称 保留时间(min)
HP1 15.694
BM1 25.420
BM1ME 31.065
BM1二聚体 32.467
BM1EE 36.038
用HPLC法3获得的各批Ribomustin的杂质分布情况见表13。
表13-用HPLC法3获得的Ribomustin的杂质分布
%面积
批号 苯达莫司汀(盐酸盐) HP1 BM1EE BM1二聚体 BM1DCE
03H08 98.14 1.07 0.21 0.34 0.03
03H07 97.67 1.5 0.2 0.33 0.04
02K27 96.93 0.93 0.29 1.18 0.08
03C08 97.61 1.24 0.19 0.46 0.02
实施例2-溶解度
通过视觉检查测定盐酸苯达莫司汀(苯达莫司汀)在水及水与不同量的甲醇、乙醇、丙醇、异丙醇、丁醇和叔丁醇(TBA)中的溶解度。在室温下制备15mg/mL苯达莫司汀,25.5mg/mL甘露醇在10mL指定醇溶液中的溶液(表1)。然后样品在5℃冷却,并在0、3、6及24小时后检查微粒和/或沉淀。
表1中概述的结果表明,苯达莫司汀的溶解度依赖于温度和水溶液中醇的量。对于所有醇,当醇的浓度增加时,苯达莫司汀的溶解度均增加。沉淀的形成也依赖于温度和时间。
同样还在含有25.5mg/mL甘露醇的20%(v/v)TBA水溶液,及含有25.5mg/mL甘露醇的30%(v/v)TBA水溶液中测定了苯达莫司汀的溶解度(图1)。将苯达莫司汀加至4mL的各溶液中,混合,直至苯达莫司汀不再溶解。使饱和溶液在-8℃、0℃、5℃或25℃下混合1小时。样品离心,重新置于初始温度下最少30分钟。将-8℃样品置于含有降低冰浴温度的氯化钠的冰浴中,在取出样品进行分析时测定温度。取各等份样品,准备进行HPLC分析。
这些实验的结果显示于图1和表2中。实验中使用的TBA的量,20%(v/v)和30%(v/v)是以本文所述稳定性研究为基础的。
如图1所示,苯达莫司汀的溶解度随着温度从25℃向0℃降低而呈线性减小。不管其是溶解在水还是溶解在水连同醇中,苯达莫司汀的溶解度都呈温度依赖性。由于苯达莫司汀的稳定性和溶解度,20%(v/v)TBA很可能是有效和加强的制药生产所需要的下限。15mg/mL苯达莫司汀的填充液接近于苯达莫司汀在5℃下的饱和限度17.2mg/mL但高于0℃的限度。30%(v/v)TBA是用于最终制剂的TBA的推荐浓度,并且不管在什么温度下均正好在溶解度限度之内。
实施例3-稳定性
A.在水中的稳定性
在室温下用水制备苯达莫司汀(15mg/mL)和甘露醇(25.5mg/mL)的溶液,并立即将其置于冰浴(以使温度迅速降低至约5℃)中10分钟,然后在5℃冷藏。在5℃储存0、3、6和24小时后,各制剂的样品经HPLC用本文所述方法进行分析。
B.在醇中的稳定性
在室温下用水制备含有15mg/mL苯达莫司汀、25.5mg/mL甘露醇和1.9%、5%、10%、20%或30%(v/v)乙醇,或者5%、10%、20%或30%(v/v)TBA、甲醇、丙醇、异丙醇或丁醇的溶液,并使其在冰浴中放置10分钟,然后在5℃冷藏。在5℃储存0、3、6和24小时后,各制剂的样品用HPLC进行分析。
C.稳定性结果
表3显示了5℃下苯达莫司汀在未加醇的水24小时的稳定性结果。苯达莫司汀在水中迅速降解,但随着醇浓度的增加,苯达莫司汀的稳定性也随之提高(图2、3和4)。尽管冻干中经常使用醇以帮助解决溶解度问题,但醇对苯达莫司汀的稳定性的影响是独特的,出人意料的,由于在保持苯达莫司汀的稳定性的条件下可以使用水溶液,因此其可以用于制造含杂质较少的苯达莫司汀。我们发现,TBA是被测试的六种醇中的最佳稳定剂(图2、3和4)。所有30%(v/v)的醇均在5℃、24小时内减少杂质HP1和二聚体的形成。就TBA而言,在5℃储存24小时后,HP1仅达到约0.4%。当用低浓度的醇配制15mg/mL苯达莫司汀并在5℃储存时,由于苯达莫司汀的沉淀及杂质的形成,因此低浓度的醇可能无效。
实施例4-制剂的优化
在测定苯达莫司汀的溶解度和稳定性之后,对冻干用制剂进行优化。由于30%TBA/水饱和溶液中苯达莫司汀的浓度与其它醇溶液相比更高,因此预计装填100mg苯达莫司汀所需要的小瓶的大小可以比现有Ribomustin的包装规格减小。尽管0℃时苯达莫司汀的饱和溶液含有18mg/mL的苯达莫司汀,但选择了15mg/mL的浓度用于制剂,以补偿由于批差异导致的大体积API纯度差异而产生的API溶解度的细微差异。为装填100mg盐酸苯达莫司汀,每个小瓶需要浓度为15mg/mL的苯达莫司汀6.67mL。
表面积(升华)体积比是生产具有良好外观、冷冻干燥迅速的冻干产品的关键。通常冻干产品占小瓶体积的30%至50%。6.67mL占20mL小瓶容量的约30%,该小瓶具有0.796cm2/mL的表面积比。
为了保持制剂与Ribomustin相似,选择甘露醇作为填充剂。进行研究就甘露醇对苯达莫司汀溶解度和产品外观的影响进行评价。甘露醇降低苯达莫司汀在乙醇和TBA水溶液中的溶解度(在15mg/mL时)。例如,含5%和10%的乙醇和TBA但不含甘露醇的溶液在24小时内不发生沉淀。然而,含有甘露醇的样品(表1)则在24小时内观察到了沉淀。含有30%(v/v)TBA、15mg/mL苯达莫司汀和25.5mg/mL甘露醇的水溶液中没有沉淀。为了保持饼状物形状良好,防止在处理期间破碎,需要最少134mg/小瓶的甘露醇,其与在含有高至200mg/小瓶甘露醇的小瓶中观察到的无差异。
所有被测试的醇均提高苯达莫司汀的稳定性和溶解度。然而,有效的摩尔分数是影响填充液的稳定性和制造的容易度所必需的。小分子醇在减低本体溶液的冰点方面效果不理想,因此需要的冻干周期长、温度低。高浓度的甲醇和乙醇产生不美观且复溶困难的饼状物。制备含有苯达莫司汀(15mg/mL)和甘露醇(25.5mg/mL)的10%乙醇、20%乙醇、10%异丙醇、20%异丙醇或30%TBA水溶液,并冻干。用10%乙醇、20%乙醇、10%异丙醇、20%异丙醇填充的冻干小瓶或者产生塌陷的饼状物,或者产生残膜。唯一产生可接受的饼状物的溶剂系统是30%TBA。此外,10%乙醇、20%乙醇、10%异丙醇、20%异丙醇冻干小瓶的复溶困难,直到大于45分钟后才完全溶解。
采用更小的小瓶的能力受到了苯达莫司汀在水/有机溶液中的浓度或溶解度的限制。在产生可接受的饼状物外观的低浓度乙醇、甲醇、丙醇和正丙醇的情况下,由于溶解度的限制,需要更稀的苯达莫司汀溶液。为了保持100mg苯达莫司汀/小瓶的规格,需要大于50mL的小瓶。并且,本文的稳定性研究表明,低醇浓度下,化学稳定性不足以允许可接受的填充时间。
影响复溶的容易度的因素之一是冻干物的孔隙率。一般来说,表面积小的无定形沉淀固体更难以溶解。只要冻干期间没有常常由于液体的蒸发(回溶)而导致的沉淀形成,大多数含有甘露醇的冻干物均在3-5分钟内复溶。根据我们对几种冻干溶剂系统的经验,并且不希望受到任何特定理论的限制,与Ribomustin复溶相关的问题可能与冻干期间由回溶导致的沉淀有关。大多数有机溶剂不能有效冻干,并由于其低熔点而导致回溶。TBA(叔丁醇)具有较高的熔点,并具有与水相比类似的蒸气压。TBA通过升华而不是蒸发的方式,以约与水相同的速率被除去。与市场上可以买到的Ribomustin需要花30-45分钟复溶相比,依照本发明用30%(v/v)TBA生产的冻干物在3-10分钟内即可复溶。
根据溶解度、稳定性、复溶和制造的容易度考虑,以下为本发明优选的冻干前制剂:盐酸苯达莫司汀约15mg/mL,甘露醇约25.5mg/mL,叔丁醇约30%(v/v)和适量注射用水。然后将该制剂在5℃下按6.67mL填充入20mL、20mm的琥珀色小瓶中,用溴化丁基胶塞塞住一部分,并装入已预冷的冻干机中。
实施例5-杂质评估
如HPLC分析测得的那样(图6),在Ribomustin的制造、混合、填充和冻干过程中引入的主要杂质是水解产物HP1、二聚体和苯达莫司汀乙酯BM1EE。BM1EE可以在原料药的制造,例如重结晶和/或纯化过程中产生。众所周知,BM1EE是比苯达莫司汀更有效的细胞毒性药物。进行实验以确定30%TBA水溶液填充液的使用是否导致苯达莫司汀叔丁酯的形成。
用形成苯达莫司汀叔丁酯所需要的传统Fisher酯化反应条件进行实验。将苯达莫司汀60℃含HCl的TBA中加热20小时。未观察到任何反应。该结果表明,在填充/整理期间形成苯达莫司汀叔丁酯应该非常困难。迄今为止,稳定性研究未在用TBA制造的药品中观察到新的杂质。
为了协助药品的测试,建立了采用反应性更高的叔丁基源的合成途径。另一种产生叔丁酯的尝试通过形成苯达莫司汀酰氯化物来完成。用草酰氯和N,N-二甲基甲酰胺处理苯达莫司汀在二氯甲烷的悬浮液。在酰氯化物形成后,将溶剂浓缩。残留物加至二氯甲烷、叔丁醇、三乙胺和4-二甲基氨基吡啶中,混合物在室温下搅拌过夜。在加入所有溶剂并纯化之后,没有得到未知化合物。LC-MS没有与苯达莫司汀叔丁酯相匹配的分子量,氢谱未显示叔丁基的峰。因此,这种尝试也未能产生苯达莫司汀叔丁酯。因此,用TBA作为共溶剂具有不与醇形成酯的额外益处。
实施例6-冻干周期的建立
实施了大量冻干周期,以分析冻干的关键阶段并获得最有效的干燥周期。进行实验就冷冻速率、第一次干燥温度、时间及压力对产品的影响进行分析。
A.冷冻速率
文献报道,TBA根据冷冻速率的不同而具有不同的晶型。在一些TBA溶液中,产品冷冻越慢,其干燥越快。缓慢冷冻期间形成的大结晶产生更大的孔,从而允许更有效的升华。然而,对苯达莫司汀的研究中,在2和8小时进行分析时,发现冷冻速率并不是关键的工艺参数。
B.第一次和第二次干燥
在第一次尝试用30%TBA溶液冻干的过程中,冻干的饼状物破碎,并且粉末从小瓶中喷出。这些饼状物看起来在冻干物中含有无定形颗粒,这是回溶的表现。当产品达到约-10℃(参见图5)时,该现象即可以重现和发生而不依赖于加热速率。为确定粉末喷出问题的原因和解决办法,对几个变量进行测试。将第一次干燥期间的压力从50μm提高至150μm,但仍然观察到了粉末喷出,只是程度要小一些。然后除了冷冻速率从2小时延长至8小时之外,重复该实验。这种改变没有任何影响。
接着分析了第一次干燥的时间长短。例如,分析了下列非常缓慢的干燥周期:在8小时内从25℃冷冻至-50℃;在-50℃保持5小时,在7小时内从-50℃加热并干燥至-25℃;在-25℃保持20小时,在2小时内从-25℃加热并干燥至-15℃,并在-15℃保持20小时,在6小时内从-15℃加热并干燥至40℃,在40℃保持20小时,同时在整个干燥过程中保持150μm的冻干室压力。未观察到粉末喷出(图5)。该周期产生了形状良好、无破碎且复溶迅速的饼状物。在不希望受到特定理论的限制的前提下,粉末喷出问题和复溶困难可能是冻干物干燥太快,从而导致强蒸气从饼状物中溢出并复溶的结果。采用侵蚀性较小的冻干周期可以重复形成美观、稳定且容易复溶的饼状物。因此,在第二次干燥之前除去所有非结合水和叔丁醇可以防止回溶和粉末喷出。在这些温和的条件下进一步优化冻干周期(图5)。在40℃一直干燥至20小时,结果未发现直接降解产物。
实施例7-冻干周期
步骤 说明 时间(小时) 温度(℃) 压力(微米)
1 保持 0.25 5℃ -
2 变温 8 -50℃ -
3 保持 4 -50℃ -
4 变温 3 -20℃ 150
5 保持 6 -20℃ 150
6 变温 1 -15℃ 150
7 保持 20 -15℃ 150
8 变温 0.5 -12℃ 150
9 保持 15.5 -12℃ 150
10 变温 15 35℃ 50
11 保持 10 35℃ 50
12 变温 1 40℃ 50
保持 5 40℃ 50
总计 89.25 - -
所有本文公开和主张的组合物及方法可以在现有公开内容的启发下无需过度不当实验即可制备和实施。虽然本发明的组合物和方法已就优选实施方案进行了描述,但是对本领域技术人员来说显而易见的是,可以在不超出本发明的精神和范围的条件下对组合物和方法以及方法的步骤或步骤的顺序进行改动。更尤其是,很显然有一些在化学和生理学上均与本文公开的溶剂有关的溶剂在达到同样或类似的结果的条件下,可以替代本文公开的溶剂。所有这类对本领域技术人员而言显而易见的相似替代和修改均被认为在由权利要求书限定的本发明的精神和范围内。
本说明书中提到的所有专利、专利申请和出版物都表明本发明所涉及领域的技术人员的水平。所有专利、专利申请和出版物均以同样的程度引入本文作为参考,就好像每个独立的出版物均特别且单独地指明引用为参考一样。
本文中说明性描述的发明可以适当地在缺乏任何本文未具体公开的要素的条件下实施。因此,例如,在本文的各种情况下,任何术语“包括”、“主要由……组成”和“由……组成”均可以与另外两个术语互换。采用的术语和表达用作说明性而非限制性的术语,并且这些术语和表达的使用并不意味着排除任何具有所显示和描述的特征的等同物或其部分,但应认识到的是,各种修改均可能在本发明权利要求的范围内。因此,应该了解的是,尽管本发明已经通过优选实施方案和任选特征具体公开,但本领域技术人员可以对本文公开的概念进行修改和变动,并且这些修改和变动均被认为在权利要求书限定的本发明的范围内。
Claims (20)
3.根据权利要求1的方法,其中所述乙醇的浓度为30%。
4.根据权利要求1的方法,其中赋形剂在冻干前加入。
5.根据权利要求4的方法,其中赋形剂是甘露醇。
6.根据权利要求1的方法,其中苯达莫司汀或盐酸苯达莫司汀浓度为2-5mg/mL。
7.冻干粉末,其根据权利要求1-6之一所述的方法获得。
8.根据权利要求1的方法,其中步骤b)包括:
i)将冻干前溶液冷冻至低于-40℃的温度,以形成冷冻溶液;
ii)使冷冻溶液保持在-40℃或低于-40℃至少2小时;
iii)将冷冻溶液缓慢调节温度至-40℃至-10℃的第一干燥温度,以形成干燥溶液;
iv)保持10至70个小时;
v)将干燥溶液缓慢调节温度至25℃至40℃的第二干燥温度;以及
vii)保持5至40个小时,以形成苯达莫司汀或盐酸苯达莫司汀冻干制剂。
9.根据权利要求8的方法,其中所述乙醇的浓度为20%至30%。
10.根据权利要求9的方法,其中所述乙醇的浓度为30%。
11.冻干粉末,其根据权利要求8-10之一所述的方法获得。
12.根据权利要求1的方法,其中步骤b)包括:
i)将冻干前溶液冷冻至-50℃,以形成冷冻溶液;
ii)使冷冻溶液保持在-50℃至少2小时至4小时;
iii)缓慢调节温度至-20℃至-12℃的第一干燥温度,以形成干燥溶液;
iv)保持在第一干燥温度10至48个小时;
v)将干燥溶液缓慢调节温度至25℃至40℃的第二干燥温度;以及
vii)保持在第二干燥温度至少5小时至20小时。
13.根据权利要求12的方法,其中所述乙醇的浓度是30%。
14.冻干粉末,其根据权利要求12-13之一所述的方法获得。
15.根据权利要求1的方法,其中步骤b)包括:i)开始在5℃的搁架温度下装载样品;ii)在8小时内冷冻至-50℃;iii)保持在-50℃4小时;iv)在3小时内调节温度至-20℃;v)在-20℃保持6小时;vi)在1小时内调节温度至-15℃;vii)保持在-15℃20小时;viii)在0.5小时内调节温度至-12℃;ix)保持在-12℃15.5小时;x)在15小时内调节温度至25℃至40℃或更高温度;xi)保持在25℃至40℃10小时;xii)在1小时内调节温度至40℃;以及xiii)保持在40℃5小时;xiv)在5℃,13.5psi的压力下卸载样品至药学上可接受的密封容器中;其中第一次干燥步骤iv,v,vi,vii,viii和ix期间的压力为150微米,第二次干燥步骤x,xi,xii和xiii期间的压力为50微米。
16.根据权利要求15的冷冻周期,其中步骤(x)在15小时内调节温度至30-35℃。
17.冻干粉末,其根据权利要求15或16的冻干周期制备得到。
18.冻干用制剂,包括浓度15mg/mL的苯达莫司汀或盐酸苯达莫司汀,浓度0-30mg/mL的甘露醇,浓度30体积%的乙醇以及水。
19.冻干制剂,其由权利要求18的制剂制成。
20.苯达莫司汀的冻干前药物组合物,包括15mg/mL的盐酸苯达莫司汀,25.5mg/mL的甘露醇,30体积%的乙醇以及水。
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CN103860482A (zh) * | 2012-12-12 | 2014-06-18 | 海口市制药厂有限公司 | 一种盐酸苯达莫司汀冻干粉针剂的制备方法、其产品及用途 |
CN103860482B (zh) * | 2012-12-12 | 2016-08-24 | 海口市制药厂有限公司 | 一种盐酸苯达莫司汀冻干粉针剂的制备方法、其产品及用途 |
CN110638765A (zh) * | 2019-11-08 | 2020-01-03 | 江苏食品药品职业技术学院 | 一种卡莫司汀冻干工艺 |
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